ES2354589T3 - MONTELUKAST PREPARATION PROCEDURE. - Google Patents

Abstract

A method of preparation of Montelukast of formula (I) by reaction of the compound of formula (III) and a compound of formula (IX), characterized in that the reaction is carried out in the presence of a base, an inert solvent and a component increasing selectivity of the process, especially of a polyether of general formula (XIII), wherein R stands for hydrogen or an alkyl and the value of n varies from 1 to 40, polyethyleneglycol of general formula (XIV), wherein n=1 to 40 or a crown-ether of formulae (XV), (XVI) or (XVII).

Description

Technical sector

  The present invention relates to a novel method of preparing montelukast of formula I, that is, a substance that is used to prepare medicaments for the treatment of asthma and allergies. 5

Prior art

  Montelukast, chemically acid [R- (E)] - 1 - [[[1- [3- [2- (7-Chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy- 1-Methylethyl) phenyl] propyl] thio] methyl] cyclopropanacetic of formula I, is a well known anti-asthmatic and anti-allergic drug. Mainly, in therapy the montelukast sodium salt described by formula II is used.

 10

Montelukast sodium salt, its preparation and various forms, amorphous or crystalline, are described in various patents or patent applications, for example, amorphous sodium montelukast is described in EP 0737186 B1 (MERCK, 1995), WO 03 / 066598 A1 (EDDY), WO 2004/108679 A1 (MOREPHEN, 2004), WO 2005/074893 A1 (CHEMAGIS). WO 2004/091618 A1 (MERCK), WO 2005/075427 A2 15 (TEVA) describes crystalline polymorphs of montelukast sodium.

  The first method of chemical synthesis of montelukast (I) was described in patent no. EP 0480717 B1 (MERCK, 1992) and later in the specialized bibliography (M. Labele, Bioorg. Med. Chem. Lett. 5 (3), 283-288 (1995)). From the point of view of the chemical synthesis of montelukast of formula I, the key step is the linking of two building blocks (intermediates) by using a newly created bond 20 between the carbon and sulfur atoms, while the configuration Absolute is maintained or completely reversed.

  In principle, there are two basic methods for carrying out the key stage of the synthesis of montelukast (I), which are indicated in scheme 1. The first method represents the formation of the CS bond, indicated as method A) in the diagram, and the second is indicated as method B). The two basic methods can be expanded with a number of variants that are mainly based on the alternation of the order of the reaction steps. The solution based on method A) is described in the following patents: EP 0480717 B1 (MERCK, 1992), EP 0737186 B1 (MERCK, 1995), US 2005/0234241 A1 (REDDY, 2005), WO 2005/105751 A1 ( TEVA, 2005), US 2005/0107612 A1 (REDDY, 2005). The solution based on method B) is described in two patent applications from SYNTHON: WO 2005/105749 A2 (SYNTHON, 2005), WO 2005/105750 A1 (SYNTHON, 2005).

  In practice, the solution that is characterized by the use of the dilithium salt of the [1- (mercaptomethyl) cyclopropyl] acetic acid of formula III-diLi is mainly used. The procedure is described in EP 0737186 B1 (MERCK, 1995); in an abbreviated form, it is described in Scheme 2. This solution also comprises a method of purification of impure montelukast of formula I through its salt with dicyclohexylamine and also a method of obtaining the sodium salt of montelukast of formula II.

  The preparation process of montelukast of formula I, as well as the quality of the product obtained, are affected by unwanted reactions to which both the raw materials and the product itself can be subjected, depending on the process conditions. The literature describes the increase in the sensitivity of the target substance to oxygen (see equation (1)), with the chemical formula (V) being described as the main product of the oxidation of montelukast of formula I (ED Nelson, J Pharm. Sci. 95, 1527-1539 (2006), C. Dufresne, J. Org. Chem. 1996, 61, 8518-8525)). Contamination of the product with this or other impurities is not convenient. For this reason, methods of preparing the target substance without oxygen are used, that is, under the protective atmosphere of an inert gas (nitrogen, for example, according to EP 0737186 B1).

  Another source of chemical contamination of montelukast is the instability of the starting material normally used and described by formula IV. This substance is mainly subject to three unwanted reactions: hydrolysis, elimination and cyclization, with the formation of impurities described by formulas 5 (VI-VIII), see scheme 3 (JO Egekeze, Anal Chem 1995, 67, 2292- 2295).

Hydrolysis can be prevented with the use of anhydrous organic solvents (for example, THF according to EP 0737186 B1), elimination can be prevented by performing the process at 10 lower temperatures (below -5 ° C, of According to EP 0737186 B1), cyclization is prevented by the use of protective groups (for example, tetrahydropyranyl (abbreviated THP), M. Labele, Bioorg. Med. Chem. Lett. 5 (3), 283-288 ( 1995)), which, however, increases the number of synthetic stages (introduction of the protective group and subsequent deprotection thereof), see scheme 4.

  The present solution represents a new and advantageous method for carrying out the key substitution reaction to obtain montelukast of formula I. The present process is distinguished from the previous solutions in the use of linear or cyclic polyethers, which guarantees a greater selectivity of the process and reduces the formation of unwanted secondary products. 5

Characteristics of the invention.

  The present invention relates to a new method for carrying out the substitution reaction that represents the key step in the montelukast preparation process of formula I. Said reaction is described by the following equation (2).

  As a starting material of the present montelukast preparation process of formula I, a substance described by general formula IX, preferably the substance of formula IV, containing the methanesulfonic group as the leaving group can be used. The starting material of formula IV is prepared, for example, in the manner described in EP 0737186 B1 (MERCK, 1995), WO 2005/105751 A1 (TEVA, 2005), according to equation (3).

  Another starting material of the present process is the [1- (mercaptomethyl) cyclopropyl] acetic acid of formula III, which is converted into the corresponding salt by the effect of two equivalents of base 10 directly in the reaction mixture. Said conversion is described by equation (4). Said salt only represents the active form of the reagent. Depending on the ion used, the characteristics of these salts differ, especially their solubility in the reaction medium. While the dilithium (III-diLi) salt is mostly soluble in the solvents used, the disodium (III-diNa) and dipotassium (III-diK) salts do not dissolve for the most part, which reduces the concentration snapshot of the active agent in the solution. The resulting effect is the deceleration of the required substitution reaction and the reduction of its selectivity.

image 1

  The process according to the present invention is further characterized by the use of bases that convert the acid of formula III into the respective salts (III-diM, where M indicates an alkali metal). As a base, various substances can be used, for example, organometallic compounds, as well as alkali metal hydroxides and alkoxides of formula X. To ensure acceptable solubility, suitable bases are alkoxides of 20 metals, particularly alkoxides characterized by a branched alkyl chain in its structure, for example, tert-butoxides and alkali metal tert-amylates (Na, K) described with formulas XI and XII.

  As a reaction medium, inert organic solvents, particularly aromatic hydrocarbons, ethers, esters, amides or sulfoxides, or mixtures thereof in any proportion can be used. For example, the following solvents are suitable: toluene, benzene, tetrahydrofuran, methyltetrahydrofuran, dimethylcarbonate, dimethylformamide or dimethyl sulfoxide. It is particularly advantageous to use a mixture of toluene and tetrahydrofuran.

  Unlike the previous solutions, the present process makes use of the advantageous properties of polyethers of general formula XIII which can be linear of formula XIV or cyclic of formulas XV-XVII. Said substances play the role of phase transfer catalysts of complexing agents that solvate metal ions, increasing the solubility and reactivity of the nucleophilic reagent 10 used, that is, the (III-diM). Increasing the reactivity of the reagent results in a greater selectivity of the process, that is, the impact of undesired competitive reactions that lead to the formation of impurities is eliminated. Thanks to the addition of polyester to the reaction mixture, the key synthetic stage takes place in a solution, not in the suspension phase.

  As suitable linear polyethers, polyethylene glycols of formula XIV 15 designated by the abbreviation PEG, which differ from one another in chain lengths or, more precisely, mixtures of polyethylene glycols specified by the average molecular weight, for example, PEG-600 or PEG-1500 Crown ethers of formulas XV-XVII, with different cycle sizes, can serve as suitable cyclic polyethers.

 twenty

  The reactions leading to the target substance of formula I were carried out in accordance with the process, according to the present invention, such that, in the first place, the carboxylic acid of formula III was mixed with the base of general formula X and the polyether of formula XIII in a medium consisting of an inert organic solvent and under an inert gas atmosphere. The obtained mixture was cooled below -5 ° C and then a solution of the substance of formula IV in a suitable organic solvent was added dropwise. In addition, the reaction mixture was stirred under an inert atmosphere at a temperature between -5 and 40 ° C for several hours, and samples were taken continuously to determine the conversion and selectivity of the substitution reaction. Finally, the impure product of formula I was isolated from the reaction medium with yields of 65-75% by common use procedures described above in EP 0737186 B1, US 2005/0234241 A1, WO 2005/105751 A1. 30

  The process according to the present invention is particularly advantageous because, due to the addition of the polyether of formula XIII to the reaction mixture, the desired reaction (substitution) is accelerated with respect to unwanted conversions (hydrolysis, elimination, cyclization). In this way, the negative influence of competitive reactions on the final composition of the reaction mixture at the end of the reaction is limited, that is, at the time of consumption of the starting substance, for example, the substance of formula IV. The cyclic or linear polyethers of the general formula XIII increase the solubility and reactivity (nucleophilia) of the reagent (III-diM), which subsequently increases the selectivity of the desired reaction. By carrying out the key stage of the preparation of montelukast of formula I, according to the present invention, the composition resulting from the reaction mixture is conveniently controlled without the need for any long-term cooling or use of protecting groups, which is a solution associated with the increase in the number of reaction stages. In addition to the limitation of the impurity content of the impure product, the present solution is also characterized by a better use of the starting substances, that is, by the fact that, in particular, the very expensive substance of formula IV is not consumed in excess because of unwanted reactions. The advantages of the present solution are demonstrated in the examples and also in figures 1 and 2, in the appendices and in table 1.

Figure 1 compares the reaction mixture composition of a reaction without the use of a cyclic or linear polyether and a reaction when these substances are added to the reaction mixture. Figure 2 compares the dependence of montelukast contents on the reaction mixtures under different conditions of the substitution reactions (according to examples 3, 4 and 6). Table 1 compares the conversions and selectivity measured after 24 hours from mixing the components in various modifications of the substitution reaction with which the montelukast of formula I is obtained according to examples 1-9.

Brief description of the figures

 Figure 1 shows HPLC chromatograms of reaction mixtures of the mesylate (IV) substitution reaction

 - A, according to example 4 after 48 hours (the component that increases the selectivity 10 of the reaction: 18-CROWN-6).

 - B, according to example 3 after 48 hours (without the addition of the component that increases the selectivity of the reactions).

 Sequence of peaks: 1. alcohol (VI), 2. mesylate (IV), 3. montelukast (I), 4. removed (VII), 5. unknown impurity, 6. cycled (VIII). fifteen

 Figure 2 shows the dependence of montelukast contents on the reaction mixture on substitution reactions carried out under different conditions (according to examples 3, 4 and 6).

Examples

  The object of the present invention is explained in greater detail from the following examples, which, however, do not limit in any sense the scope of the present invention, defined in the claims. twenty

EXAMPLE 1 (reference example)

  In 20 ml of toluene, the [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g) and the base (lithium tert-butoxide, 0.31 g) were mixed, and the mixture was stirred under argon and cooled to about -10oC. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml was added from tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to the laboratory temperature over one hour. It was then stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 2 (reference example)

  In 20 ml of toluene, [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g), base 30 (lithium tert-butoxide, 0.31 g), and 12-CROWN-4 (0 , 33 g), and the mixture was stirred under argon and cooled to about -10 ° C. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml was added from tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to laboratory temperature over one hour. It was then stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 3 (reference example)

  In 20 ml of toluene, the [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g) and the base (sodium tert-butoxide, 0.36 g) were mixed, and the mixture was stirred under argon and cooled to about -10oC. Next, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-40 propanol (1 g) in 5 ml of tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to laboratory temperature over one hour. It was then stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 4 45

  In 20 ml of toluene, [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g), base (sodium tert-butoxide, 0.36 g), and 18-CROWN-6 (0, 50 g), and the mixture was stirred under argon and cooled to about -10 ° C. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml was added from tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to laboratory temperature over one hour. Then, it was stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 5

  In 20 ml of toluene, [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g), base (sodium tert-butoxide, 0.36 g), and 15-CROWN-5 (0, 41 g), and the mixture was stirred under argon and cooled to about -10 ° C. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml was added from tetrahydrofuran to the suspension obtained. The reaction mixture was stirred progressively from -10 ° C to laboratory temperature over one hour. It was then stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 6

  In 20 ml of toluene, [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g), base 10 (sodium tert-butoxide, 0.36 g), and PEG-600 (1.1 were mixed) g), and the mixture was stirred under argon and cooled to about -10 ° C. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml was added from tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to laboratory temperature over one hour. It was then stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 7

  In 20 ml of toluene, [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g), base (sodium tert-butoxide, 0.36 g), and PEG-1500 (2.7 g) were mixed ), and the mixture was stirred under argon and cooled to about -10 ° C. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-20 methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml of tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to laboratory temperature over one hour. It was then stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 8 (reference example) 25

  In 20 ml of toluene, the [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g) and the base (potassium tert-amylate, 0.42 g) were mixed, and the mixture was stirred under argon and cooled to about -10oC. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml was added from tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to laboratory temperature over one hour. It was then stirred at a laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC.

EXAMPLE 9

  In 20 ml of toluene, [1- (mercaptomethyl) cyclopropyl] acetic acid (0.28 g) and base (potassium tert-amylate, 0.42 g), and 18-CROWN-6 (0, 50 g), and the mixture was stirred under argon and cooled to approximately -10 ° C. Then, a solution of 2- (3- (S) - (3- (2- (7-chloroquinolinyl) -etenyl) phenyl) -3-methanesulfonyloxypropyl) phenyl-2-propanol (1 g) in 5 ml was added from tetrahydrofuran to the suspension obtained. The reaction mixture was progressively stirred from -10 ° C to laboratory temperature over one hour. It was then stirred at the laboratory temperature (approximately 21 ° C) for several hours. The reaction mixture was continuously analyzed by HPLC. 40

Table 1. Conversions and comparative selectivities after 24 hours from the mixing of the components in different modifications of the substitution reaction with which montelukast is obtained (I)

 Sample no.

 Component that increases reaction selectivity Conversion (%) Selectivity (%)

 one

 ----- 97.9 60.8

 2

 12-CROWN-4 97.3 59.6

 3

 ----- 82.3 26.0

 4

 18-CROWN-6 96.1 79.0

 5

 15-CROWN-5 94.6 77.5

 6

 PEG-600 93.2 81.1

 7

 PEG-1500 81.4 68.2

 8

 ----- 95.0 9.6

 9

 18-CROWN-6 92.7 51.5

DESCRIPTION OF THE ANALYTICAL METHOD

The conversions and selectivities in the present montelukast preparation procedure were determined by the application of the HPLC method. The chromatograms were measured with the EliteLachrom device, manufactured by the Hitachi company. As a mobile phase, a mixture of acetonitrile (80%) and a 0.1 M aqueous solution of ammonium formate adjusted to pH 3.6 with formic acid (20%) was used. The measurements were carried out in an isocratic mode, the flow of the mobile phase being 1.5 ml / min.

Claims (10)

  1. Method of preparing montelukast of formula I, by reacting the compound of formula III with a compound of formula IX,   characterized in that the reaction is carried out in the presence of a base, an inert solvent and a component that increases the selectivity of the process, in which a polyether of the general formula XIII is used as a component that increases the process selectivity   where R represents hydrogen or an alkyl and the value of n ranges from 1 to 40, or a crown ether described by the formula (XV), (XVI) or (XVII) 10   and using said base as an alkali metal alkoxide described by the general formula R’OM, in which R ’represents an alkyl group and M represents an alkali metal selected from the group consisting of Na or K.   2. Method according to claim 1, characterized in that a polyethylene glycol of the general formula XIV is used as the component that increases the process selectivity, in which n = 1 to 40.   3. Method according to claim 1, characterized in that a substance of formula (IV) is used as the starting substance, in which Ms represents the methanesulfonyl leaving group.   4. Method according to claim 1, characterized in that an alkali metal alkoxide described by the general formula (XI) or (XII) is used as the base, wherein M represents an alkali metal selected from the group consisting of Na and K .  5   5. Method according to any one of claims 1 to 4, characterized in that an aromatic hydrocarbon, an ether, an ester, an amide or a sulfoxide, or mixtures thereof in any proportion is used as an inert organic solvent.   Method according to claim 5, characterized in that toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl carbonate, dimethylformamide or 10 dimethyl sulfoxide, or mixtures thereof in any proportion are used as inert organic solvent.   7. Method according to claim 6, characterized in that a mixture of toluene and tetrahydrofuran is used as an inert organic solvent.   Method according to any one of claims 1 to 7, characterized in that the carboxylic acid of formula (III) is first mixed with a base of general formula (X) and a polyether of formula (XIII) in the environment of an inert organic solvent and under an inert gas atmosphere, then the mixture obtained is cooled and a solution of the substance (IV) in an organic solvent is added dropwise, the reaction mixture is further stirred under the inert gas atmosphere until the consumption of the starting substances.    9. Method according to claim 8, characterized in that the reaction components are mixed with cooling, preferably below -5 ° C, and then the reaction is continued at 20 temperatures of the reaction mixture, from -5 to + 40 ° C , preferably at the laboratory temperature, from 20 to 25 ° C.